We have recently developed a modified simian immunodeficiency virus (SIV) that is susceptible to HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). Prior attempts to make such a virus have met with limited success. We elected to use the SIVmne proviral backbone in our studies and have replaced the SIV RT with HIV-1 RT. In vitro studies of the modified SIV isolate indicates that it replicates efficiently and is sensitive to NNRTIs. We are now testing the relative fitness of these modified isolates, their stability in long-term culture, and the types of resistance mutations that are engendered when they are placed under selective pressure. We also plan to evaluate replication of the NNRTI-sensitive SIV isolates in a macaque model as well as test the fitness of antiviral-resistant and parental isolates. We are performing these studies in collaboration with the section of Dr. Stephen Hughes in the HIV Drug Resistance Program.